Use of atii antagonist for the treatment or prevention of metabolic syndrome

ABSTRACT

The present invention relates to the use of an angiotensin II type 1 receptor antagonist alone, or in combination with a metabolically neutral antihypertensive substance, for the prevention and/or treatment of the metabolic syndrome.

FIELD OF THE INVENTION

The present invention relates to the use of an angiotensin II type 1receptor antagonist alone, or in combination with a metabolicallyneutral antihypertensive substance, for the prevention and/or treatmentof the metabolic syndrome.

BACKGROUND OF THE INVENTION

The metabolic syndrome [JAMA 2001; 285:2486-97] is characterised by highlevels of blood fats, high blood pressure, insulin resistance, andcentral obesity (excessive fat tissue in the abdominal region). Subjectssuffering from the metabolic syndrome are also at an increased risk ofcoronary artery disease and other arteriosclerotic conditions as well asdiabetes. It has been proposed that the metabolic syndrome may begenetically based. However, the underlying cause of the disorder is notyet fully understood.

The combination of an angiotensin II type 1 receptor antagonist with acalcium antagonist is known from WO00/02543 A2. The combination has beenproposed for use in the treatment of inter alia hypertension, congestiveheart failure and myocardial infarction.

The use of a combination of a certain renin inhibitor and at least onetherapeutic agent selected from inter alia an AT1-receptor antagonistand an angiotensin converting enzyme inhibitor for the treatment ofinter alia diabetic retinopathy, syndrome X and isolated systolichypertension has been proposed in WO02/40007 A1.

OUTLINE OF THE INVENTION

The present invention relates to the use of an angiotensin II type 1receptor antagonist alone, or in combination with a metabolicallyneutral antihypertensive substance, for the prevention and/or treatmentof metabolic syndrome.

The Metabolic Syndrome

The metabolic syndrome is herein defined in accordance with thedefinition of the World Health Organization, i.e. according to thefollowing criteria [World Health Organization (WHO). Department ofNoncommunicable Disease Surveillance. Geneva: WHO 1999 pp 1-59]:

-   1. Fasting plasma glucose above 6.1 mmol/L-   2. Blood pressure above 140/90 mm Hg-   3. One or more of the following:    -   a) plasma triglycerides above 1.7 mmol/L and/or HDL below 0.9        mmol/L (men), below 1.0 mmol/L (women)    -   b) Body mass index above 30 kg/m²        Fasting Plasma Glucose Level

The fasting plasma glucose level is defined as the concentration ofglucose in the plasma of a subject after an overnight's fast. Patientswere instructed not to eat breakfast on the morning of the follow-upvisits.

Blood Pressure

Blood pressure is defined as the pressure of the blood on the walls ofthe arteries and is dependent on the energy of the heart action, theelasticity of the walls of the arteries, and the volume and viscosity ofthe blood. The maximum pressure occurs near the end of the stroke outputof the left ventricle of the heart and is termed maximum or systolicpressure. The minimum pressure occurs late in ventricular diastole andis termed minimum or diastolic pressure.

Blood Fats—Plasma Triglycerides

Cholesterol and triglycerides are transported in the body fluids in theform of lipoprotein particles. Lipoproteins are classified according todensity: chylomicrons, chylomicron remnants, very low densitylipoproteins (VLDL), intermediate-density lipoproteins (IDL),low-density lipoproteins (LDL) and high-density lipoproteins (HDL).

Obesity

Obesity is defined herein as a body mass index (BM) above 30 kg/m². Thebody mass index is calculated as (body weight in kilograms)/(length inmeters)².

Angiotensin II Type 1 Receptor Antagonists

Angiotensin II type 1 receptor antagonists are compounds which are knownto interfere with the renin-angiotensin system (RAS) and are used totreat common cardiovascular diseases, particularly arterial hypertensionand congestive heart failure.

In one aspect of the present invention use is made of an angiotensin IItype 1 receptor antagonist of the general formula I:

wherein A is selected from the group consisting of

or pharmaceutically acceptable salts, solvates or stereochemical isomersof any of these, or solvates of such salts.

The compound of the general formula I wherein A is the I:1 moiety hasthe generic name losartan and is known from European Patent No. EP 0 253310 B1 to du Pont.

The compound of the general formula I wherein A is the I:5 moiety hasthe generic name candesartan cilexetil and is known from European PatentNo. 459 136 B1 and U.S. Pat. No. 5,196,444 to Takeda ChemicalIndustries.

The compound of the general formula I wherein A is the I:9 moiety hasthe generic name irbesartan.

The compound of the general formula I wherein A is the I:13 moiety hasthe generic name candesartan and is known from European Patent No. 459136 B1 and U.S. Pat. No. 5,703,110 of Takeda Chemical Industries.

Further examples of angiotensin II type 1 receptor antagonists arevalsartan, olmesartan, telmisartan and eprosartan.

In one aspect of the present invention, use is made of a compound of thegeneral formula I wherein A is I:5 (candesartan cilexetil) or A is I:13(candesartan). Candesartan cilexetil is currently manufactured and soldworldwide e.g. under the trade names Atacand®, Amias® and Blopress®.

When the angiotensin II type 1 receptor antagonists used in the presentinvention have several asymmetric carbon atoms, they can exist inseveral stereochemical forms. The present invention includes the mixtureof isomers as well as the individual stereoisomers. The presentinvention further includes geometrical isomers, rotational isomers,enantiomers, racemates and diastereomers.

Where applicable, the angiotensin II type 1 receptor antagonists may beused in neutral form, e.g. as a carboxylic acid, or in the form of asalt, preferably a pharmaceutically acceptable salt such as the sodium,potassium, ammonium, calcium or magnesium salt of the compound at issue.Where applicable the compounds listed above can be used in hydrolyzableester form.

Normally, the angiotensin II type 1 receptor antagonists areadministered by the oral or parenteral route, e.g. by intravenous,subcutaneous or intramuscular administration. Other possible routes ofadministration include rectal and transdermal administration. Theformulation may be given in dosage unit form, especially as tablets orcapsules.

The adjuvants, diluents and carriers used in the pharmaceuticalformulations of the present invention, may be conventional ones wellknown to the person skilled in the art. Examples of such adjuvants,diluents and carriers include substances used as binders, lubricants,fillers, disintegrants, pH regulants and thickeners as well assubstances included for providing isotonic solutions.

The wording “daily dose” is defined so that the angiotensin II type 1receptor antagonist may be given either as a unit dosage once daily,such as a tablet or a capsule, or alternatively the angiotensin II type1 receptor antagonist may be given twice daily. The daily dose may varywithin the dosage ranges mentioned below, and depends on the patient'sindividual response to treatment.

With the wording “therapeutic treatment” as herein used, is meant thatthe metabolic syndrome is treated by administering an angiotensin IItype 1 receptor antagonist according to the formula I above. This meansthat the use of an angiotensin II type 1 receptor antagonist accordingto the formula I above, provides therapy of a fully or partly developedmetabolic syndrome.

With the wording “prophylactic treatment” as herein used, is meant thatan angiotensin II type 1 receptor antagonist according to the formula Iabove, may be administered to a person to prevent the metabolicsyndrome.

The dose of the angiotensin II type 1 receptor antagonist and inparticular a compound according to formula I to be administered inprophylaxis and/or treatment of metabolic syndrome in subjects sufferingfrom, or susceptible to, such conditions, will depend primarily upon theangiotensin II type 1 receptor antagonists used, the route ofadministration, the severity of the condition to be treated and thestatus of the subject at issue. The daily dose, especially at oral,rectal as well as parenteral administration, can be in the range of fromabout 0.01 mg to about 1000 mg per day of active substance, such as from0.1 mg to 750 mg per day of active substance or from 1 mg to 500 mg perday of active substance. In one embodiment, where candesartan andderivatives thereof are used, including candesartan cilexetil, thedosage range at oral, rectal as well as parenteral administration can bein the range of from about 0.1 mg to about 300 mg per day, such as from0.2 mg to 200 mg or from 4 mg to 160 mg per day calculated ascandesartan.

Metabolically Neutral Antihypertensive Substances

Metabolically neutral antihypertensive substances are compounds capableof reducing hypertension without influencing metabolic profile of thesubject being treated. One example from this group is calcium receptorantagonists. Calcium receptor antagonists influence the inflow ofcalcium ions into cells, in particular into the cells of smooth muscles.The calcium antagonists are essentially dihydropyridines or ornon-dihydropyridines, such as diltiazem-type or verapamil-typecompounds. Examples of dihydropyridine calcium antagonists areamlodipine, verapamil, nifedipine, nimodipine, diltiazem, nicardipine,felodipine, emlodipine, ryosidine, lacidipine, niguldipine, niludipine,nisoldipine, nitrendipine, nivaldipine and isradipine, as well as, ineach case, a pharmaceutically acceptable salt thereof. Examples ofnon-dihydropyridine calcium antagonists are flunarizine, diltiazem,mibefradil, prenylamine, fendiline, gallopamil, verapamil, tiapamil andanipamil, as well as, in each case, a pharmaceutically acceptable saltthereof.

The dose of the metabolically neutral antihypertensive, such as of acalcium receptor antagonist to be administered in prophylaxis and/ortreatment of metabolic syndrome in subjects suffering from, orsusceptible to, such conditions, will depend primarily upon themetabolically neutral antihypertensive used, the route ofadministration, the severity of the condition to be treated and thestatus of the subject at issue. The daily dose, e.g. at oral, rectal orparenteral administration, can be in the range of from about 1 mg toabout 1000 mg per day of active substance, such as from 5 mg to 200 mgper day of active substance.

EXAMPLES

A clinical study was performed. It was a study with a double-blind,randomised, controlled, parallel group design.

For inclusion, sitting blood pressure should be in the range of 140-179and/or 90-104 mm Hg (mean of two measurements according to standardisedprocedures [1999 World Health Organization (WHO)—International Societyof Hypertension Guidelines for the Management of Hypertension. Journalof Hypertension 1999; 17; 151-83] and at two visits) on placebotreatment and after the patients had been subjected tonon-pharmacological treatment, as recommended [The Swedish Council onTechnology Assessment in Health Care (SBU). Moderately elevated bloodpressure. J Intern Med 1995; 238(Suppl 737): S1-S128; 1999 World HealthOrganization (WHO)—International Society of Hypertension Guidelines forthe Management of Hypertension. Journal of Hypertension 1999; 17;151-83] for one month or longer. Since the non-pharmacologicalintervention had been introduced before the start of the study and thenmaintained, its effect on metabolic variables during the study wasminimal.

Exclusion criteria included: compelling indication for any particularantihypertensive drug, contraindication for any antihypertensive drug,need of lipid lowering drug therapy, severe concomitant disease,diabetes mellitus, substance abuse, or any other condition associatedwith poor compliance.

After four weeks of single-blind treatment with placebo, the patientswere randomised to double-blind treatment with either candesartancilexetil 16 mg or hydrochlorothiazide 25 mg and followed for one year.If sitting systolic or diastolic blood pressure was above targetpressure (<130/<85 mmHg, for patients below 65 years, or <140/<90 mmHg,if 65 years or older) [1999 World Health Organization(WHO)—International Society of Hypertension Guidelines for theManagement of Hypertension. Journal of Hypertension 1999; 17; 151-83] atany visit during the treatment period, double-blind treatment withfelodipine extended-release 2.5-5.0 mg was added to the candesartangroup and atenolol 50-100 mg was added to the hydrochlorothiazide group.No further antihypertensive treatment was allowed. Two patients werewithdrawn from the study, both in the candesartan cilexetil group, sincetheir blood pressure exceeded the pre-specified safety level (≧180and/or ≧105 mm Hg, mean of two recordings at different visits).

To ensure that 324 patients would complete the study, it was estimatedthat 400 patients needed to be randomised. In all, 393 patients wererandomised, 197 to candesartan cilexetil and 196 to hydrochlorothiazide;one patient was excluded due to lack of outcome data and was thereforenot included in the intention-to-treat analyses. The discontinuationrates were low, 8.2 and 7.1%, respectively. No patient was lost tofollow-up. In all, 370 patients out of 392 (94.4%) had never beentreated with antihypertensive drugs and were thus truly newly detectedhypertensives. The other 22 patients had not been drug-treated forhypertension six months before the study but short treatment periods intheir past could not be excluded. Three patients (0.8%), two in thecandesartan cilexetil group and one in the hydrochlorothiazide group,received lipid-lowering therapy during part of the study period and werethus protocol violators. These patients were included in theintention-to-treat but not in the per-protocol analyses.

Glucose Analyses in All Patients

Analyses of plasma glucose were carried out at the Department ofClinical Chemistry, Umeå University Hospital. Plasma glucose wasroutinely analysed by Vitros 950 glucose oxidase method (Ortho ClinicalDiagnostics).

Lipid Analyses in All Patients

Total plasma cholesterol, LDL-cholesterol, HDL-cholesterol andtriglycerides were determined in all patients at randomisation (n=392),and in most patients after six months (n=354), and after 12 months(n=352). Total plasma cholesterol and triglycerides concentrations weredetermined enzymatically. HDL-cholesterol was measured after theprecipitation of apolipoprotein B-containing lipoproteins in wholeplasma by heparin-manganese chloride [Lipid Research Clinics Program:Manual of Laboratory Operations, Bethesda, Md.: National Institutes ofHealth, Vol 1. Lipid and Lipoprotein Analysis. DHEW publ, 1974].VLDL-cholesterol was assumed to equal one fifth of the plasmatriglyceride concentration and LDL-cholesterol level was determined bydifference according to the method of Friedewald et al [Friedewald W T,Levy R I, Fredrickson D S. Estimation of the concentration oflow-density lipoprotein cholesterol in plasma, without use of thepreparative ultracentrifuge. Clin Chem 1972; 18:499-502]; four patientshad triglyceride values above 4.8 mmol/L (400 mg/dL). Their LDLcholesterol levels were not calculated.

The Metabolic Syndrome

The metabolic syndrome was diagnosed according to the following criteria[World Health Organization (WHO). Department of Noncommunicable DiseaseSurveillance. Geneva: WHO 1999 pp 1-59]:

-   -   1. Fasting plasma glucose above 6.1 mmol/L    -   2. Blood pressure above 140/90 mm Hg    -   3. One or more of the following:        -   a. plasma triglycerides above 1.7 mmol/L and/or HDL below            0.9 mmol/L (men), below 1.0 mmol/L (women)        -   b. Body mass index above 30 kg/m²            Statistical Analyses

Efficacy variables were analysed using analysis of covariance (ANCOVA)with treatment and health centre as factors and baseline value ascovariate. Difference in treatment effect was estimated with 95%confidence interval. To test difference between treatments in change ofbiochemistry variables the Wilcoxon Rank Sum test was used. With 324patients completing the study it had an 80% power of detecting adifference in change from baseline to 12 months of 0.25 mmol/L in plasmaLDL cholesterol between the groups, based on a significance level of 5%and an estimated standard deviation of the difference in change of 0.8mmol/L. All efficacy variables were analysed according to theintention-to-treat approach. In this approach all randomised patientswho had completed the study and had taken at least one dose of studydrug were included.

Results

Drug Usage and Blood Pressure

In the candesartan cilexetil group, 29% were on monotherapy at the endof study whereas 71% needed add-on treatment with felodipine (meandosage 3 mg). The corresponding figures in the hydrochlorothiazide groupwere 16% and 84% (atenolol, mean dosage 68 mg), respectively. Bothtreatment regimens lowered the blood pressure well (see table 1 below).After one year, 65% in the candesartan cilexetil group and 62% in thehydrochlorothiazide group attained a blood pressure <140/<90 mm Hg.Blood pressure at the start of the non-pharmacological treatment period,one month or more before randomisation, was 158/98 mm Hg, i.e.approximately 3/1 mm Hg higher than the randomisation pressures. TABLE 1Change of blood pressure and heart rate at 6 and 12 months with 95%confidence interval of estimate and test of difference in change betweentreatments. Candesartan cilexetil HCTZ 95% confidence (n = 196) (n =196) interval P-value At 6 months, sitting SBP (mm Hg), mean change−20.9 (13.1) −23.9 (13.0) +0.5 to +5.0 0.02 DBP (mm Hg), mean change−12.8 (6.9)  −13.9 (7.1)  −0.2 to +2.4 0.09 Heart rate (bpm), meanchange −2.1 (8.4) −6.8 (10.1) +3.0 to +6.4 <0.001 At 12 months, sittingSBP (mm Hg), mean change −21.0 (15.2) −22.8 (14.9) −1.2 to +4.1 >0.20DBP (mm Hg), mean change −13.0 (7.4)  −12.9 (7.7)  −1.6 to +1.2 >0.20Heart rate (bpm) mean change −2.2 (8.4) −7.3 (9.4) +3.5 to +6.7 <0.001*Data are mean (SD).Bpm = beats per minute,DBP = diastolic blood pressure,SBP = systolic blood pressure.Serum Insulin, Plasma Glucose and Oral Glucose Tolerance Test

Fasting levels of both serum insulin and plasma glucose increased duringtreatment in the hydrochlorothiazide group in contrast to unaffectedlevels in the candesartan cilexetil group (see table 2 below). TABLE 2Insulin and glucose at baseline and 12 months with 95% confidenceinterval of estimate and test of difference in change betweentreatments. Data are mean (SD) Candesartan cilexetil HCTZ 95% confidence(n = 196) (n = 196) interval P-value S-insulin (mlU/L) Baseline 9.25(7.90) 9.65 (6.09) At 12 months 8.96 (5.42) 11.00 (6.88)  Mean change at12 months −0.30 (6.50)  1.35 (6.09) −2.91 to −0.61 0.003 P-glucose(mmol/L) Baseline 5.17 (0.58) 5.29 (0.98) At 12 months 5.10 (0.57) 5.42(0.89) Mean change at 12 months −0.06 (0.46)  0.13 (0.69) −0.34 to −0.12<0.001 S-insulin/P-glucose Baseline 1.77 (1.38) 1.83 (1.10) At 12 months1.76 (1.06) 2.03 (1.23) Mean change at 12 months −0.00 (1.23)  0.20(1.13) −0.44 to 0.00  0.05Metabolic Syndrome

At 12 months, 18 patients in the hydrochlorothiazide group vs. only fivein the candesartan cilexetil group suffered from the ‘metabolicsyndrome’, as defined by WHO (p=0.007); at base-line the correspondingfigures were 12 and 13, respectively. The changes in fasting plasmaglucose and plasma triglycerides are shown in table 3 below. TABLE 3Fasting plasma glucose levels and plasma triglycerides at baseline andafter 12 months for patients in the candesartan cilexetil groupsuffering from the metabolic syndrome at baseline but not after 12months of treatment. Patient Fasting glucose (mmol/L) Triglycerides(mmol/L) number Baseline 12 months Baseline 12 months 1 6.4 5.9 2 6.15.5 3 6.5 5.7 2.15 1.59 4 2.34 1.44 5 6.2 5.7 6 6.2 5.6 2.65 1.28 7 6.25.2 8 6.2 6.0

1-10. (canceled)
 11. A method for the treatment and/or prevention ofmetabolic syndrome, whereby a pharmaceutically and pharmacologicallyeffective amount of an angiotensin II type 1 receptor antagonist aloneor in combination with a metabolically neutral antihypertensivesubstance is administered to a subject in need of such treatment orprevention.
 12. The method of claim 11, wherein the angiotensin II type1 receptor antagonist is of the general formula I:

wherein A is

or pharmaceutically acceptable salts, solvates or stereochemical isomersthereof of any of these, or solvates of such salts.
 13. The method ofclaim 12, wherein A is I:5.
 14. The method of claim 12, wherein A isI:13.
 15. The method of any one of claims 11-14, wherein themetabolically neutral antihypertensive substance is a calciumantagonist.
 16. The method of claim 15, wherein the metabolicallyneutral antihypertensive substance is selected from amlodipine,verapamil, nifedipine, nimodipine, diltiazem, nicardipine, felodipine,emlodipine, ryosidine, lacidipine, niguldipine, niludipine, nisoldipine,nitrendipine, nivaldipine, isradipine, flunarizine, diltiazem,mibefradil, prenylamine, fendiline, gallopamil, verapamil, tiapamil andanipamil, as well as, in each case, or a pharmaceutically acceptablesalt thereof.
 17. The method of any one of claims 11-14, wherein thedaily dose of the angiotensin II type 1 receptor antagonist is fromabout 0.01 mg to about 1000 mg.
 18. The method of claim 17, wherein thedaily dose of the angiotensin II type 1 receptor antagonist is fromabout 0.1 mg to 750 mg.
 19. The method of claim 18, wherein the dailydose of the angiotensin II type 1 receptor antagonist is from about 1 mgto 500 mg.
 20. The method of claim 13, wherein the daily dose of theangiotensin II type 1 receptor antagonist is from about 0.1 mg to about300 mg per day calculated as candesartan.